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DK2798064T3 - Fremstilling og anvendelse af in vitro-syntetiseret ssrna til indføring i pattedyrceller til induktion af en biologisk eller biokemisk virkning - Google Patents

Fremstilling og anvendelse af in vitro-syntetiseret ssrna til indføring i pattedyrceller til induktion af en biologisk eller biokemisk virkning Download PDF

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DK2798064T3
DK2798064T3 DK12815983.7T DK12815983T DK2798064T3 DK 2798064 T3 DK2798064 T3 DK 2798064T3 DK 12815983 T DK12815983 T DK 12815983T DK 2798064 T3 DK2798064 T3 DK 2798064T3
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protein
cell
rna
dsrna
mrna
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DK12815983.7T
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Judith Meis
Anthony Person
Cynthia Chin
Jerome Jendrisak
Gary Dahl
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Cellscript Llc
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Claims (15)

1. Sammensætning eller system, som omfatter: a) enkeltstrenget RNA (ssRNA), som koder et protein, hvor ssRNA er et produkt af in vitro-transkription af et DNA-template ved en RNA-polymerase; b) et dobbeltstrenget RNA-specifikt endoribonuclease-lll-protein; og c) magnesiumkationer, som er til stede i en koncentration på tilnærmelsesvis 1-4 mM.
2. Sammensætning eller system ifølge krav 1, hvor: i) magnesiumionerne er til stede i en koncentration på tilnærmelsesvis 1-3 mM; og/eller ii) sammensætningen eller systemet yderligere omfatter et salt eller anden forbindelse i en tilstrækkelig koncentration for at bibeholde en ionisk styrke svarende til mindst tilnærmelsesvis 50 mM kaliumacetat eller kaliumglutamat.
3. Sammensætning eller system ifølge et af kravene 1 eller 2, hvor ssRNA er kendetegnet ved mindst en af følgende: i) koder en transkriptionsfaktor; ii) koder et CD-protein, det vil sige et protein, der er identificeret i clusteret i et differentieringssystem; iii) koder et enzym; iv) koder et protein i den immunglobuline superfamilie; v) koder et cytokin eller kemokin; vi) koder et celleoverfladereceptorprotein; vii) koder et protein i en cellesignalvej; viii) koder et antistof; ix) koder en T-cellereceptor; x) koder et protein, som reducerer eller undertrykker en iboende immunreaktion omfattende interferon (IFN)-produktion eller -reaktion såsom mRNA, der koder B18R-protein eller vaccinevirus E3L- eller K3L-protein; xi) koder et reporterprotein; xii) indeholder et eller flere modificerede ribonukleosider, herunder hvor det modificerede ribonukleosid er udvalgt fra gruppen bestående af pseudouri-din, 1-methyl-pseudouridin, 5-methylcytidin, 5-methyluridin, 2'-0-methyluridin og 2-thiouridin i stedet for mindst en del af det tilsvarende umodificerede kanoniske ribonukleosid; xiii) udviser en cap-struktur; xiv) udviser en Cap 1-struktur, hvor 5'-penultimatnukleotidet omfatter en 2'-0-methyl-ribosylgruppe; xv) udviser en poly A-hale; xvi) er fri for modificerede ribonukleosider bortset fra de ribonukleosider, som omfatter 5' -cap-strukturen, hvis en 5' cap er til stede, herunder 5'-penultimatnukleosidet, når den in vitro-syntetiserede ssRNA udviser en cap 1-struktur; xvii) udviser mindst en heterolog sekvens udvalgt blandt: en 5' UTR-sekvens, Kozak-sekvens, en IRES-sekvens og 3' UTR-sekvens; xviii) koder en omprogrammeringsfaktor eller en iPS-celleinduktionsfaktor; xix) koder ikke et protein eller polypeptid, men omfatter i stedet mindst en lang ikke-kodende RNA (ncRNA); xx) koder mindst et protein udvalgt fra gruppen bestående af: MYOD, ASCL1, MYT1L, NEUROD1, POU3F2, OCT4, SOX2, KLF4, LIN28, NANOG, MYC, c-MYC, c-MYC(T58A), L-MYC, ETS2, MESP1 GATA4, HAND2, TBX5, MEF2C, ASCL1, EN1, FOXA2, LMX1A, NURR1, PITX3, HNF1.alpha., FINF4.alpha., FOXA 1, FOXA2, FOXA3, GATA4, erythropoietin og et CD-protein; eller et funktionelt fragment eller variant ifølge et af de foregående; xxi) koder a protein; xxii) koder et funktionelt protein; xxiii) koder et protein, som er til stede på eller i en cellemembran; xxiv) koder et immunt effektorprotein; xxv) koder et komplementært protein i et immunsystem i et hvirveldyr; og xxvi) koder et protein, som omfatter en receptor for en signalvej.
4. Sammensætning eller system ifølge et af kravene 1-3, hvor mindre end 0,001 % af massen af RNA i sammensætningen er dsRNA med en størrelse på mere end tilnærmelsesvis 40 basepar i længden.
5. Sammensætning ifølge et af de foregående krav a) til anvendelse som et medikament, hvor medikamentet fortrinsvis anvendes inden for områderne af regenerativ medicin, celleomprogrammering, cellebaserede terapier, enzymerstatningsterapier, cellevæv og organtransplantation eller -reparation, væv eller organkonstruktion og immunterapier; eller b) til anvendelse inden for behandlingen af et menneske eller dyr for at inducere en biologisk eller biokemisk virkning, hvor den biologiske eller biokemiske virkning omfatter - omprogrammering af celler, som udviser en første differentieret tilstand eller fænotype til celler, som udviser en anden differentieret tilstand eller fænotype, herunder dedifferentiering, transdifferentiering og differentiering eller re-differentiering; - kompensering for et manglende eller defekt protein; - eksprimering af et ønsket protein såsom en transkriptionsfaktor, cellesignaleringsprotein, vækstfaktor, interferon, interleukin, cluster af differentierings (CD)-molekyle, proteinhormon, proteinreceptor eller et antistof; - eksprimering af et langt ikke-kodende RNA-molekyle, som er involveret i differentiering; - udløsning af en sygdomsspecifik immunreaktion.
6. Fremgangsmåde til behandling af en RNA-sammensætning omfattende eller bestående af in vitro-syntetiseret ssRNA eller mRNA for at generere en behandlet RNA-sammensætning, hvilken fremgangsmåde omfatter: at bringe RNA-sammensætningen eller den in vitro-syntetiserede ssRNA eller mRNA i kontakt med en bufferet vandig opløsning omfattende et dobbeltstrenget RNA-specifikt endoribonuklease-lIl-protein, magnesiumkationer i en koncentration på tilnærmelsesvis 1-4 mM og et salt, der giver en ionisk styrke svarende til mindst tilnærmelsesvis 50 mM kaliumacetat eller kaliumglutamat, og inkubering på sådanne betingelser, at en behandlet RNA-sammensætning genereres.
7. Fremgangsmåde ifølge krav 6, yderligere omfattende rensning af RNA-sammensætningen eller ssRNA eller mRNA ved fjernelse af mindst en af endoribonuklease I Il-reaktionskomponenterne og dens nukleotidfordøjelses-produkter.
8. Fremgangsmåde ifølge et af kravene 6 eller 7, hvor RNA-sammensætningen eller ssRNA eller mRNA er kendetegnet ved mindst en af de følgende: i) koder en transkriptionsfaktor; ii) koder et CD-protein, det vil sige et protein, der er identificeret i clusteret i et differentieringssystem; iii) koder et enzym; iv) koder et protein i den immunglobuline superfamilie; v) koder et cytokin eller kemokin; vi) koder et celleoverfladereceptorprotein; vii) koder et protein i en cellesignalvej; viii) koder et antistof; ix) koder en T-cellereceptor; x) koder et protein, som reducerer eller undertrykker en iboende immunreaktion omfattende interferon (IFN)-produktion eller -reaktion såsom mRNA, der koder B18R-protein eller vaccinevirus E3L- eller K3L-protein; xi) koder et reporterprotein; xii) indeholder et eller flere modificerede ribonukleosider, herunder hvor det modificerede ribonukleosid er udvalgt fra gruppen bestående af pseudouri-din, 1-methyl-pseudouridin, 5-methylcytidin, 5-methyluridin, 2'-0-methyluridin, 2-thiouridin og N6-methyladenosin i stedet for mindst en del af det tilsvarende umodificerede kanoniske ribonukleosid; xiii) udviser en cap-struktur; xiv) udviser en Cap 1-struktur, hvor 5'-penultimatnukleotidet omfatter en 2'-0-methyl-ribosylgruppe; xv) udviser en poly A-hale; xvi) er fri for modificerede ribonukleosider bortset fra de ribonukleosider, som omfatter 5' -cap-strukturen, hvis en 5' cap er til stede, herunder 5'-penultimatnukleosidet, når den in vitro-syntetiserede ssRNA udviser en cap 1-struktur; xvii) udviser mindst en heterolog sekvens udvalgt blandt: en 5' UTR-sekvens, Kozak-sekvens, en IRES-sekvens og 3' UTR-sekvens; xviii) koder en omprogrammeringsfaktor eller en iPS-celleinduktionsfaktor; xix) koder ikke et protein eller polypeptid, men omfatter i stedet mindst en lang ikke-kodende RNA (ncRNA); xx) koder mindst et protein udvalgt fra gruppen bestående af: MYOD, ASCL1, MYT1L, NEUROD1, POU3F2, OCT4, SOX2, KLF4, LIN28, NANOG, MYC, c-MYC, c-MYC(T58A), L-MYC, ETS2, MESP1 GATA4, HAND2, TBX5, MEF2C, ASCL1, EN1, FOXA2, LMX1A, NURR1, PITX3, HNF1.alpha., HNF4.alpha., FOXA1, FOXA2, FOXA3, GATA4, erythropoietin og et CD-protein; eller et funktionelt fragment eller variant ifølge et af de foregående; xxi) koder a protein; xxii) koder et funktionelt protein; xxiii) koder et protein, som er til stede på eller i en cellemembran; xxiv) koder et immunt effektorprotein; xxv) koder et komplementært protein i et immunsystem i et hvirveldyr; og xxvi) koder et protein, som omfatter en receptor for en signalvej.
9. Fremgangsmåde ifølge et af kravene 6-8, hvorved mindre end 0,001 % af massen af RNA i den behandlede RNA-sammensætning er dsRNA med en størrelse på mere end tilnærmelsesvis 40 basepar i længden.
10. Ex vivo- eller in vitro-fremgangsmåde til at opnå translation af mindst et protein af interesse i en menneske- eller dyrecelle, hvilken fremgangsmåde omfatter: gentagne gange eller kontinuerligt at føre en RNA-sammensætning ind i cellen, omfattende mRNA, som koder det mindst ene protein af interesse, hvor RNA-sammensætningen er blevet behandlet med RNase III ifølge et af de foregående krav, hvor mindre end 0,001 % af massen af RNA i sammensætningen er dsRNA med en størrelse på mere end tilnærmelsesvis 40 basepar i længden, og dyrke cellen på betingelser, hvor cellen overlever og vokser, og hvor mRNA translateres.
11. Fremgangsmåde ifølge krav 10, hvorved cellen udviser en første differentieret tilstand eller fænotype før indføringen og udviser en anden differentieret tilstand eller fænotype efter indføringen.
12. Fremgangsmåde til fremstilling af en behandlet RNA-sammensætning omfattende eller bestående af in vitro-syntetiseret ssRNA eller mRNA, hvilken fremgangsmåde omfatter at bringe en reaktionsblanding, som omfatter RNA-sammensætningen eller ssRNA eller mRNA, i kontakt med et dsRNA-specifikt endoribonuklease lll-protein, magnesiumkationer i en koncentration på tilnærmelsesvis 1-4 mM og i et salt, som resulterer i en ionstyrke mindst lige så høj som kaliumacetat i en koncentration på tilnærmelsesvis 50-300 mM på sådanne betingelser, at en behandlet RNA-sammensætning genereres; a) herunder hvor: i) fremgangsmåden yderligere omfatter oprensning af ssRNA-molekylerne i den behandlede RNA-sammensætning, f.eks. ved saltudfældning, PAGE, agarose-gelelektroforese, søjlekromatografi eller HPLC, hvor de fordøjede dsRNA kontaminantmolekyler fjernes; eller ii) fremgangsmåden ikke omfatter en søjlekromatografi, hverken tyngdekraftstrømning eller under tryk, elektroforese eller andet separationstrin omfattende anvendelse af en resin, gel eller membran; b) og herunder hvor ssRNA eller mRNA iii) indeholder mindst et modificeret ribonukleosid, udvalgt fra gruppen bestående af pseudouridin, 1-methyl-pseudouridin, 5-methylcytidin, 5-methyluridin, 2'-0-methyluridin, 2-thiouridin og N6-methyladenosin i stedet for mindst en del af det tilsvarende umodificerede kanoniske ribonukleosid, som reducerer induktionen eller aktiveringen af en RNA-sensor eller iboende immunreaktionsvej i en celle; eller iv) er fri for modificerede ribonukleosider bortset fra disse ribonukleosider, som omfatter 5' cap-nukleotidstrukturen, hvis 5' cap er til stede, herunder 5'-penultimatnukleosidet, når den in vitro-syntetiserede ssRNA udviser en caplcap-struktur, hvis til stede;
13. Fremgangsmåde ifølge krav 12, hvorved mindre end 0,001 % af massen af RNA i den behandlede RNA-sammensætning er dsRNA med en størrelse på mere end tilnærmelsesvis 40 basepar i længden.
14. Ex-vivo- eller in-vitro-fremgangsmåde til at opnå en eksprimering af mindst et protein af interesse i en celle, hvilken fremgangsmåde omfatter: at bringe en celle i kontakt med en RNA-sammensætning, som omfatter in vitro-syntetiseret RNA, som koder mindst et protein af interesse ifølge et af de foregående krav, hvor mindre end 0,001 % af massen af RNA i sammensætningen er dsRNA med en størrelse på mere end tilnærmelsesvis 40 basepar i længden, således at det mindst ene protein af interesse eksprimeres i cellen, hvor kontakteringen: a) udføres mindst en gang dagligt i flere dage eller b) udføres flere gange i et tidsrum på mindst 24 timer; og c) ikke inducerer en iboende immunreaktion, som: i) dræber cellen; ii) er tilstrækkelig til at inhibere proteinsyntese med det dobbelte eller mere; og/eller iii) inducerer eller aktiverer proteiner, som er involveret i en apoptosevej.
15. Fremgangsmåde ifølge krav 14, hvor det mindst ene protein af interesse er en omprogrammeringsfaktor eller transkriptionsfaktor, og hvor de flere dage er et tilstrækkeligt antal af dage for at omprogrammere cellen, herunder hvor: d) cellen er en somatisk menneske- eller pattedyrcelle, hvilken omprogrammeringsfaktor eller transkriptionsfaktor er en iPSC-induktionsfaktor, udvalgt fra gruppen bestående af OCT4, SOX2, KLF4, LIN28, NANOG og et MYC familieprotein valgt blandt vildtypen c-MYC, mutant c-MYC(T58A) og L-MYC, og cellen omprogrammeres til en iPS-celle; eller e) cellen er en ikke-myoblast menneske- eller pattedyrcelle, det mindst ene protein af interesse er MYOD-protein eller et funktionelt fragment eller variant deraf, og cellen omprogrammeres til en myoblastcelle; eller f) cellen er et somatisk ikke-neuron menneske- eller pattedyrcelle, det i det mindste ene protein af interesse er udvalgt fra gruppen bestående af: ASCL1, MYT1L, NEUROD1 og POU3F2 eller funktionelt fragment eller variant af en hvilken som helst deraf, og cellen omprogrammeres til en neuron celle; og/eller g) fremgangsmåden i henhold til et hvilket som helst fra d) til f) udføres, hvor cellen er til stede i et dyrkningsmedium, som er frit for feeder-celler; og/eller h) fremgangsmåden i henhold til et hvilket som helst fra d) til f) udføres uden anvendelse af et eksogent protein, siRNA, eller et lille molekylemiddel, som inhiberer eller reducerer aktiveringen, induktionen eller eksprimering af et eller flere proteiner i en iboende immunreaktionsvej; og/eller i) fremgangsmåden i henhold til et hvilket som helst fra d) til f), hvor den in vitro-syntetiserede RNA indeholder mindst et modificeret ribonukleosid udvalgt fra gruppen bestående af pseudouridin, 1-methyl-pseudouridin, 5-methylcytidin, 5-methyluridin, 2'-0-methyluridin og 2-thiouridin; eller j) fremgangsmåden i henhold til et hvilket som helst fra d) til f), hvor den in vitro-syntetiserede RNA ikke indeholder modificerede ribonukleosider bortset fra de ribonukleosider, som omfatter 5' cap- nukleotidstrukturen, herunder 5' penultimatnukleosidet, når den in vitro-syntetiserede RNA udviser en cap1 cap-struktur, hvis til stede.
DK12815983.7T 2011-12-30 2012-12-31 Fremstilling og anvendelse af in vitro-syntetiseret ssrna til indføring i pattedyrceller til induktion af en biologisk eller biokemisk virkning DK2798064T3 (da)

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